A detailed understanding of human biology will require not only knowledge of the human genome but also of the human metagenome, defined here as the ensemble of the genomes of human-associated microorganisms. Our proposal focuses on the microorganisms of the gut, which are particularly abundant and complex and have an important role for human health and well-being. We shall implement and integrate the following activities: (i) creation of a reference set of genes and genomes of intestinal microbes, using high fidelity metagenomic sequencing and full genome sequencing of selected bacterial species; (ii) creation of the generic tools, based on the high density DNA arrays and novel ultra-high throughput re-sequencing techniques, to study the variation of human gut microbiota; (iii) use of the tools to search for correlations between the genes present in the gut microbiota and disease, focusing on the inflammatory bowel disease and obesity, the two pathologies of increasing social relevance in Europe; (iv) study of the genes correlated with the disease, both in terms of their function in microbes and their effect on the host, with the focus on host-microbe interactions; (v) development of an informatics resource to store and organize the heterogeneous information generated within the project, such as gene and genome sequences, gene frequencies in healthy and sick individuals or gene functions and also enriched by information relevant to human gut microbiota from the outside of the project; (vi) creation of the bioinformatics tools to carry out the meta-analysis of the information; (vii) creation of an interface with the stakeholders, including an international board to promote cooperation and coordination in the human metagenome field, and general public. Our project will place Europe in a leading position in this field and open avenues to modulate human gut microbiota in a reasoned way, enabling to optimize the health and wellbeing of any individual.